Globulol from Alpinia oxyphylla Miq. Enhances the pharmacological effects of anti-PD-1 drugs in combination by reducing PD-L1 expression in hepatocellular carcinoma.

INTRODUCTION: Globulol is a terpenoid metabolite isolated from Alpinia oxyphylla Miq. Previous studies have demonstrated that terpenoid metabolites exhibit anti-inflammatory, antioxidant, and antitumor activities. However, the exact mechanisms by which Globulol impacts HCC remain obscure. MATERIALS AND METHODS: The influence of Globulol on HCC cell lines was assessed in vitro employing the CCK8, EdU cell proliferation assays, a three-dimensional tumor spheroid model, and flow cytometry. The combination effects of Globulol and anti-PD-1 was explored in an HCC and CD8(+)T cell co-culture model. The molecular pathways influenced by Globulol in HCC were delineated through transcriptomic sequencing, molecular docking, bioinformatics approach, cell transfection, quantitative reverse transcription-PCR, and Western blot analysis. RESULTS: Globulol notably decreased the viability of Huh1/Huh7 cells in a concentration-dependent manner. It was found to prompt the secretion of the chemokine CCL4 by tumor cells, enhancing the infiltration of cytotoxic CD8(+)T cells into the HCC microenvironment. Further research has indicated that globulol inhibits PD-L1 expression by targeting the PAK4-pAKT-STAT3 axis, improves the immunosuppressive microenvironment of HCC, and enhances the pharmacological effects in combination with Tislelizumab. CONCLUSION: These results suggest that Globulol can promote a microenvironment permissive to PD-1 blockade, thereby exerting anti-HCC activity. Hence, the combination of Globulol and PD-1 blockade may be a promising strategy for HCC treatment.